Methods and compositions for modulating BK channel activity and vasodilation

Abstract

Methods and compositions are provided for modulating myocyte BK channel activity and for screening for modulators of BK channel activity. The methods and compositions are useful in the treatment of disorders where increasing myocyte BK channel activity can attenuate, revert or prevent the disorder. For example, the methods and compositions are useful for treating disorders ameliorated by increasing vasodilation and blood flow in a subject, in particular, increasing cerebral blood flow.

1 . A method of screening candidate compositions for an ability to modulate myocyte BK channel activity, the method comprising:
 (a) establishing a test sample comprising a myocyte BK channel β 1  subunit; and   (b) measuring the interaction, effect, or combination thereof, of a candidate composition on the test sample to thereby determine the ability of the candidate composition to modulate myocyte BK channel activity.   
     
     
         2 . The method of  claim 1 , wherein the candidate composition comprises a lithocholate, or an analog or derivative thereof. 
     
     
         3 . The method of  claim 2 , wherein the myocyte is a small resistance artery myocyte. 
     
     
         4 . A method of screening for candidate compositions useful in the treatment of a disorder where increasing myocyte BK channel activity can attenuate, revert or prevent the disorder, the method comprising:
 (a) establishing a test sample comprising a myocyte BK channel β 1  subunit; and   (b) measuring the interaction, effect, or combination thereof, of a candidate composition on the test sample to thereby determine the ability of the candidate composition to increase myocyte BK channel activity and attenuate, revert or prevent the disorder.   
     
     
         5 . The method of  claim 4 , wherein the candidate composition comprises a lithocholate, or an analog or derivative thereof. 
     
     
         6 . The method of  claim 4 , wherein the myocyte is a small resistance artery myocyte. 
     
     
         7 . The method of  claim 4 , wherein the attenuation, reversion or prevention of the disorder is mediated at least in part through modulation of blood pressure and/or blood flow. 
     
     
         8 . The method of  claim 4 , wherein the attenuation, reversion or prevention of the disorder is mediated at least in part through vasodilation. 
     
     
         9 . The method of  claim 8 , wherein the vasodilation is characterized by an increase in blood vessel diameter of about 10 percent. 
     
     
         10 . A method of treating a subject having a disorder, the method comprising, administering to the subject a composition comprising a compound capable of increasing myocyte BK channel activity mediated by the BK channel by subunit, wherein increasing myocyte BK channel activity can attenuate, revert or prevent the disorder. 
     
     
         11 . The method of  claim 10 , wherein the compound comprises a lithocholate, or an analog or derivative thereof. 
     
     
         12 . The method of  claim 10 , wherein the administration of the composition comprising the compound capable of increasing myocyte BK channel activity results in decreases in blood pressure and/or increases in blood flow. 
     
     
         13 . The method of  claim 12 , wherein the increase in blood flow is mediated at least in part through vasodilation. 
     
     
         14 . The method of  claim 13 , wherein the vasodilation occurs at least in part in small resistance arteries. 
     
     
         15 . The method of  claim 14 , wherein the small resistance arteries are small cerebral arteries. 
     
     
         16 . The method of  claim 15 , wherein the vasodilation in the small cerebral arteries is about a 10 percent increase in arterial diameter. 
     
     
         17 . The method of  claim 16 , wherein the increase in blood flow in the small cerebral arteries is about 30 percent. 
     
     
         18 . A pharmaceutical composition useful for increasing myocyte BK channel activity in a subject, wherein the composition comprises an effective amount of a lithocholate or an analog or derivative thereof; and a pharmaceutically acceptable carrier. 
     
     
         19 . A pharmaceutical composition useful for increasing myocyte BK channel activity in a subject, wherein the BK channel activity is mediated by the BK channel β 1  subunit. 
     
     
         20 . A method of selectively targeting tissues comprising BK channel β 1  subunits in a subject, the method comprising administering to the subject a composition comprising a compound capable of selectively binding myocyte BK channel β 1  subunits, whereby tissues comprising BK channel β 1  subunits are targeted. 
     
     
         21 . The method of  claim 20 , wherein the composition comprises a lithocholate, or an analog or derivative thereof. 
     
     
         22 . The method of  claim 20 , wherein the tissues targeted are smooth muscle tissues. 
     
     
         23 . The method of  claim 20 , wherein the composition further comprises an imaging agent. 
     
     
         24 . The method of  claim 20 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         25 . The method of  claim 20 , wherein the subject is a mammal.